Ammonolysis of 2-nitro-6-oximino cyclohexanone

ABSTRACT

2-NITRO-6-OXIMINO CYCLOHEXANONE CAN BE REACTED WITH ANHYDROUS AMMONIA IN A SOLVENT SELECTED FROM THE GROUP CONSISTING OF C1 TO C4 ALKANOLS AND C4 TO C8 ALIPHATIC AND ALICYCLIC MONO- OR DI-ETHERS TO AFFORD 2-OXIMINO-6NITRO-CAPROMIDE, A PRECURSOR OF LYSINE.

United States Patent f 3,803,231 AMMONOLYSIS 0F 2-NlTRO-6-0XIMINOCYCLOHEXANONE Robert Fuhrmann, Morris Plains, Fred W. Kofi, Clifton, andJohn Pisanchyn, Morristown, N.J., assignors to Allied ChemicalCorporation, New York, N.Y.

No Drawing. Original application Dec. 11, 1970, Ser. No. 97,290. Dividedand this application Jan. 18, 1973, Ser. No. 324,689

Int. Cl. C07c 97/02 U.S. Cl. 260-561 R 3 Claims ABSTRACT OF THEDISCLOSURE 2-nitro-6-oximino cyclohexanone can be reacted with anhydrousammonia in a solvent selected from the group consisting of C to Calkanols and C to C aliphatic and alicyclic monoor di-ethers to afford2-oximino-6- nitro-caproamide, a precursor of lysine.

This is a Division of application Ser. No. 97,290, filed Dec. 11, 1970.

BACKGROUND OF THE INVENTION This invention relates to a process for thepreparation of a precursor of lysine, one of the essential amino acidsuseful as a dietary supplement. More particularly, this inventionrelates to a process for the preparation of 2-0ximino-6-nitro-caproamide (Compound I) by ammonolysis of2-nitro-6-oximino cyclohexanone. The compound2-oximino-6-nitrocaproamide can be transformed into lysine by reductionof the nitro and oximino groups thereof to amino groups followed byhydrolysis of the amide to the free acid, i.e.

l CH2(CH )3CH( JOH 1) reduction OH 2) hydrolysis NH: NH:

(I) lysine The prior art contains much teaching of various syntheticroutes to lysine. All clearly suffer from one or more shortcomings sincenone have achieved widespread commercial acceptance. Specifically, afacile synthesis of lysine utilizing cheap, commercially availablestarting materials is not yet known to the art. Lysine amide is resolvedinto its optical isomers and thereafter transformable into thecorresponding lysine isomer by known prior art methods. Lysine amide isalso a very desirable compound per se for the reason it can be readilyresolved into the biologically active L-isomer and the separatedD-isomer racemized. Since L-lysine amide itself is nutritionallyvaluable, it need not be transformed into L-lysine. The instantinvention is therefore directed to a novel compound which is a precursorof lysine amide and also to a process for the preparation of said novelcompound from 2-nitro-6-oximino cyclohexanone.

The synthetic route, which entails starting with the known compounda-nitro cyclohexanone, is as follows:

II M

-NO: HON: N01

nitrosating agent tag. 1

II (I) HON= N0g YET (|3.Hz(CH2)aCCNH 3 N02 NOH 3,803,231 Patented Apr.9, 1974 The instant invention is directed to process step 2 in theabove-indicated reaction sequence and to novel Compound I. In additionto being a precursor of lysine amide, Compound I is an efifectivefungicide. The starting material for process step 2 is 2-nitro-6-oxjminocyclohexanone (Compound II), which is obtained by reactingu-nitrocyclohexanone with a nitrosating agent such as alkyl nitrites,nitrogen oxides, nitrosylformate or nitrosyl chloride in an inertsolvent such as diglyme. Compound II is not reported in the prior artliterature, however, it can be readily prepared as described above andseparated from the inert solvent by evaporating oil the latter,preferably at reduced pressure. Compound II is a pale yellow solidhaving a melting point of 160 C. Compound II and its preparation aredescribed in copending commonly assigned U.S. patent application Ser.No. 852,947, now U.S. Pat. 3,681,460 and Ser. No. 852,881, now abandonedboth filed Aug. 25, 1969*.

The transformation of Compound II into Compound I is effected bycontacting the former with a sufficient quantity of anhydrous ammonia inthe presence of a solvent selected from the group consisting of C to Calkanols and C., to C aliphatic and alicyclic monoor diethers.Contacting Compound II with anhydrous ammonia in the absence of solventaffords substantial amounts of by-product. Reaction with ammonia in thepresence of water affords an intractable complex mixture of products,possibly including Compound I. Examples of the above-indicated suitablesolvents include methanol, ethanol, isopropanol, n-butanol, t-butanol,diethyl ether, di-isopropyl ether, glyme, diglyme, diethyl carbitol,tetrahydrofuran and dioxan. The preferred solvents are glyme(dimethoxyethane), t-butanol, and dioxan. Mixtures of any of the abovesolvents can also be used.

The amount of ammonia reacted with Compound II is not critical, providedat least one mole of ammonia per mole of Compound II is present.Preferably from 5.0 to about 25.0 moles of ammonia per mole of Compound11 will be present. Greater than 25.0 moles of ammonia has nodeleterious effect but provides no increase in reaction rate or yield.The amount of solvent present can suitably vary from about 1.0 to 20.0parts by weight per part of 2-nitro-6-oximino cyclohexanone. Greaterthan 20 parts by weight of solvent per part of Compound 11 is notdeleterious but serves no useful purpose and is inconvenient in that itmust be removed from the product.

The ammonolysis reaction can suitably be carried out at any temperatureranging from about 20 C. up to about 150 C., at which temperature somedecomposition ofthe 2-nitr0-6-oximino cyclohexanone commences. It ispreferred that the reaction be carried out at a temperature ranging fromabout 40 to C. Since this is above the boiling point of ammonia (-33),such reaction temperatures require a closed pressure vessel. Ordinarily,the preferred reaction procedure entails placing the desired quantitiesof ammonia, solvent, and 2-nitro-6-oximino cyclohexanone in a reactionvessel, sealing same, and then bringing the vessel contents to thedesired temperature. As above indicated, use of a closed vessel andtemperatures above the ammonia boiling point result in developing asuper atmospheric pressure in the reaction vessel, which pressure will,of course, vary with temperature and the volume of reactants and vessel.However, the reaction pressure is not critical and appears to have nosubstantial effect on reaction rate or product yield and purity.

Preferably, the reaction vessel will be fabricated of, or lined withglass or other inert material to prevent any possible contamination ofthe product.

The reaction time is not critical and ordinarily, complete ammonolysiswill be effected within a period of from about /2 to 24 hours, the exactperiod of time being dependent primarily on the reaction temperature.Longer reaction times ordinarily serve no useful purpose.

While we do not wish to be bound by any particular mechanisticinterpretation, it is believed that when the reaction solvent is a C toC alkanol, the reaction proceeds by the following sequence of reactions.

HON=

wherein R is a C to C alkyl group.

If 2-nitro-6-oximino cyclohexanone (Compound II) is reacted with a C toC alkanol in the absence of ammonia, novel Compound IV is obtained andcan be isolated. Reaction of Compound IV with ammonia affords CompoundI.

When the reaction solvent is a C to C aliphatic or alicyclic monoordi-ether, a stable intermediate such as Compound IV is probably notbeing formed. No reaction of Compound II with such ether occurs in theabsence of ammonia.

Isolation and purification of Compound I from the reaction mixturecontaining solvent and any unreacted excess ammonia is most suitablyefiected by evaporation of the solvent and ammonia, preferably atreduced pressure, and then recrystallizing the residue which comprisesessentially crude Compound I. The preferred recrystallization solvent isa chlorinated alkane, particularly preferred is dichloro ethane. PureCompound I is a yellow crystalline solid of M.P. 96.597.5.

The yield obtained when preferred reaction conditions are utilized isessentially quantitative.

The invention can be more fully understood by reference to the followingexamples. All parts are parts by weight unless otherwise expresslynoted.

4 EXAMPLE 1 Ammonolytic cleavage of 2-oximino-6-nitro cyclohexanone To a6 oz. Fischer & Porter aerosol compatability tube was charged 8.3 gramsof 2-oximino-6-nitro cyclohexanone and 80 ml. of dioxane. Stirring waseffected with a magnetic stirring bar at room temperature to achievesolution. The reaction vessel (tube) and charge was purged of air byfive pressurizations with N followed by venting to atmospheric pressure.The reaction vessel was then placed in a heated silicone oil bath andthe temperature brought up to 62 C. At this temperature, the reactor waspressurized with ammonia to 110 p.s.i.g. Immediate precipitation of theammonium salt of 2-oximino- 6-nitro cyclohexanone occurred. Stirring wascontinued together with repressurizations with ammonia until completesolution of the precipitated salt occurred. After 5.75 hours ofreaction, heating was terminated, the reaction mixture cooled to roomtemperature, and the ammonia vented. The solution was then flashevaporated at reduced pressure in a Buchler rotating flash evaporator toobtain 9.10 grams of solids (theoretical is 9.08 grams). The dry, crudeproduct was recrystallized from ethylene dichloride aifording 8.00 gramsof the pure product, 2- oximino-G-nitro hexanamide (88.7 yield). Therecrystallized product was shown to be free of the starting material andany other impurity by thin-layer chromatography.

EXAMPLE 2 Additional runs were made utilizing the reaction and work-upprocedures of Example 1. Results are tabulated below.

Run No 1 Charge:

N00, parts by weight 2.01 Solvent Ammonia, parts by Weight.-..

Reaction parameters:

Time, hours Temperature, C Weight ratio NHa/NO C M01 ratio NHa/NOOSolvent/N wt. rat-i0 Product, mol percent yield ONE (2-oximino-6- nitrohexariamide) 1 Tetrahydrotura-n.

EXAMPLE 3 Approx- Reaction imate product Mole ratio Wt. ratio Time Temp.yield, NH3:NOG solvent=NOG Solvent (hrs.) C.) percent 10. 0 18 25 94 12.0 16 25 95 15. 0 10 50 96 25. 0 5 50 96 10. 0 5 5 75 95 17. 0 5 1. 5 8085 12. 0 5 1. 5 75 84 10. 0 2. 0 1. 0 2O 5O 3. 0 3. 0 24 20 70 2. 0 4. 010 78 2. 0 3. 0 10 60 84 12. 0 3. 0 5 60 92 6. 0 3. 0 5 60 85 6. 0 3. 05 60 89 8. 0 3. 0 5 60 91 7. 5 5. 0 3 120 95 1. 5 3.0 5 70 ll. 5 2. 0 583 17 5. 0 3 84 15 8 t-Butauol 5 Now.Glyme=dimethoxy ethane;THF=tetrahydrofuram parts by weight per part of 2-nitro-6-oximinocyclohexa- 5 none of a solvent selected from the group consisting of Cto C alkanols and C to C aliphatic and alicyclic monoand di-ethers at atemperature ranging from about 20 C. to 150 C.

2. A process in accordance with claim 1 wherein said 10 solvent is a Cto C aliphatic or alicyclic diether.

3. A process in accordance with claim 1 wherein said temperature rangesfrom about 40 to 120 C.

References Cited FOREIGN PATENTS 1,203,540 8/1970 Great Britain 260-482LORRAINE A. WEINBERGE-R, Primary Examiner P. J. KILLOS, AssistantExaminer US. Cl. X.R.

260-482 R, 534 L, 561 A, 566 A; 424-320

